Correlation of adrenomedullin with the erythropoietin receptor and microvessel density in hepatocellular carcinoma

Introduction

Uncontrolled angiogenesis plays an essential role in the occurrence, metastasis and malignant progression of hepatocellular carcinoma (HCC). This study aimed to investigate the expression of adrenomedullin (ADM) in human HCC and its correlation with the expression of erythropoietin receptor (EPOR), microvessel density (MVD) and the tumor pathological characteristics.

Material and methods

Fresh tumor tissues were obtained from 30 HCC patients after hepatectomy. Ten cirrhotic and 10 normal liver tissues were included as controls. Expression of ADM and EPOR was determined by real-time PCR. The MVD was determined by counting the number of microvessels.

Results

The MVD and the mRNA levels of ADM and EPOR in cancer tissues were significantly higher than those in the non-cancer tissues (p < 0.05). Expression of ADM was significantly correlated with the MVD and EPOR (r = 0.68 and 0.74, p < 0.01). Adrenomedullin and EPOR mRNA levels in HCC tissues were correlated with capsule invasion, pathological differentiation and tumor metastasis (p < 0.05).

Conclusions

Our findings suggest that ADM and EPOR may serve as new regulatory factors involved in angiogenesis of HCC and represent novel targets for the treatment of HCC.     

The influence of extracts from Peucedanum salinum on the replication of adenovirus type 5

Introduction

The aim of the study was to examine the cytotoxicity and evaluate the antiviral and virucidal activity of methanol and methanol/H₂O extracts from the herb of Peucedanum salinum. Plants belonging to the genus Peucedanum (Apiaceae family) have been used in traditional medicine for a long time.

Material and methods

The examination of the cytotoxicity of the extracts in the concentrations of 0.1, 0.2, 0.5, 1, 2, 4 mg/ml was carried out on the cell culture line HEK-293. Cytotoxicity of the examined extracts was measured by the colorimetric MTT (tetrazolium) method. After determination of the highest non-toxic concentration of examined extracts, antiviral and virucidal activity against adenovirus type 5 (Adenoviridae) was established.

Results

The non-toxic doses were as follows: 1 mg/ml of methanol extract and 2 mg/ml of methanol/H₂O extract (1 : 1 v/v). Antiviral activity was observed for the methanol extract of Peucedanum salinum in concentrations of 0.5 and 1 mg/ml. The extract caused the decrease of titre of the virus by 2 log and 1.33 log, respectively. The methanol/H₂O extract (1 : 1 v/v) decreased the titre of the virus by 1.33 log and 1.5 log in concentrations of 1 and 2 mg/ml, respectively. The examined extracts had no virucidal activity against adenovirus type 5.

Conclusions

The examined extract is a new, potentially active source of active substances possessing antiviral activity and further studies are needed.     

A double-blind,randomized phase II study of dicycloplatin plus paclitaxel versus carboplatin plus paclitaxel as first-line therapy for patients with advanced non-small-cell lung cancers

Introduction

The aim of this study was to compare the efficacy and toxicity of dicycloplatin plus paclitaxel with those of carboplatin plus paclitaxel as first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC).

Material and methods

In this study, 240 NSCLC patients with stage IIIB (with pleural effusion) and stage IV disease were randomly assigned (1: 1) to receive dicycloplatin 450 mg/m² or carboplatin AUC = 5, in combination with paclitaxel 175 mg/m² (D + P or C + P) every 3 weeks for up to 4 to 6 cycles. The primary endpoint was response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and adverse events.

Results

The response rates for the D + P and C + P arm were 36.44% and 30.51%, respectively (p = 0.33). The median PFS was 5.6 months in the D + P arm and 4.7 months in the C + P arm (p = 0.31). The median OS was 14.9 months for D + P and 12.9 months for C + P (p = 0.37). Adverse events in the two arms were well balanced. The most common grade 3/4 adverse event was hematologic toxicity.

Conclusions

Patients treated with D + P had similar response and survival rates to those treated with C + P, and toxicities of both treatments were generally tolerable.     

Prognostic importance of some clinical and therapeutic factors for the effect of portal vein embolization in patients with primarily inoperable colorectal liver metastases

Introduction

Portal vein embolization (PVE) may increase the resectability of liver metastases. However, the problem of PVE is insufficient growth of the liver or tumor progression in some patients. The aim of this study was to evaluate the significance of commonly available clinical factors for the result of PVE.

Material and methods

Portal vein embolization was performed in 38 patients with colorectal liver metastases. Effects of age, gender, time between PVE and liver resection, oncological therapy after PVE, indocyanine green retention rate test, synchronous, metachronous and extrahepatic metastases, liver volume before and after PVE, increase of liver volume after PVE and the quality of liver parenchyma before PVE on the result of PVE were evaluated.

Results

Liver resection was performed in 23 (62.2%) patients within 1.3 ±0.4 months after PVE. Tumor progression occurred in 9 (23.7%) patients and 6 (15.8%) patients had insufficient liver hypertrophy. Significant clinical factors of PVE failure were number of liver metastases (cut-off – 4; odds ratio – 4.7; p < 0.03), liver volume after PVE (cut-off 1000 cm³; odds ratio – 5.1; p < 0.02), growth of liver volume after PVE (cut-off 150 cm³; odds ratio – 18.7; p < 0.002), oncological therapy administered concomitantly with PVE (p < 0.003).

Conclusions

Negative clinical factors of resectability of colorectal cancer liver metastases after PVE included more than four liver metastases, liver volume after PVE < 1000 cm³, growth of the contralateral lobe by less than 150 cm³ and concurrent oncological therapy.     

Unilobar Versus Bilobar Biliary Drainage: Effect on Quality of Life and Bilirubin Level Reduction

Background:

Percutaneous biliary drainage is an accepted palliative treatment for malignant biliary obstruction.

Purpose:

To assess the effect on quality of life (QOL) and bilirubin level reduction in patients with inoperable malignant biliary obstruction treated by unilobar or bilobar percutaneous transhepatic biliary drainage (PTBD).

Materials and Methods:

Over a period of 2 years, 49 patients (age range, 22–75 years) of inoperable malignant biliary obstruction were treated by PTBD. Technical and clinical success rates, QOL, patency rates, survival rates, and complications were recorded. Clinical success rates, QOL, and bilirubin reduction were compared in patients treated with complete (n = 21) versus partial (n = 28) liver parenchyma drainage. QOL before and 1 month after biliary drainage were analyzed retrospectively between these two groups.

Results:

Biliary drainage was successful in all 49 patients, with an overall significant reduction of the postintervention bilirubin levels (P < 0.001) resulting in overall clinical success rate of 89.97%. Clinical success rates were similar in patients treated with whole-liver drainage versus partial-liver drainage. Mean serum bilirubin level before PTBD was 19.85 mg/dl and after the procedure at 1 month was 6.02 mg/dl. The mean baseline functional score was 39.35, symptom scale score was 59.55, and global health score was 27.45. At 1 month, mean functional score was 61.25, symptom scale score was 36.0 4, and global health score was 56.33, with overall significant improvement in QOL (<0.001). There was a statistically significant difference in the improvement of the QOL scores (P = 0.002), among patients who achieved clinical success, compared with those patients who did not achieve clinical success at 1 month. We did not find any significant difference in the QOL scores in patients according to the amount of liver drained (unilateral or bilateral drainage), the type of internalization used (ring biliary or stent). Overall, minor and major complications rates were 14.3% and 8.1%, respectively.

Conclusion:

Percutaneous biliary drainage provides good palliation of malignant obstructive jaundice. Partial-liver drainage achieved results as good as those after complete liver drainage with significant improvements in QOL and reduction of the bilirubin level.     

The Efficacy of Endoscopic Palliation of Obstructive Jaundice in Hepatocellular Carcinoma

Purpose

Obstructive jaundice in patients with hepatocellular carcinoma (HCC) is uncommon (0.5-13%). Unlike other causes of obstructive jaundice, the role of endoscopic intervention in obstructive jaundice complicated by HCC has not been clearly defined. The aim of this study was to evaluate the clinical characteristics of obstructive jaundice caused by HCC and predictive factors for successful endoscopic intervention.

Materials and Methods

From 1999 to 2009, 54 patients with HCC who underwent endoscopic intervention to relieve obstructive jaundice were included. We defined endoscopic intervention as a clinical success when the obstructive jaundice was relieved within 4 weeks.

Results

Clinical success was achieved in 23 patients (42.6%). Patients in the clinical success group showed better Child-Pugh liver function (C-P grade A or B/C; 17/6 vs. 8/20), lower total bilirubin levels (8.1±5.3 mg/dL vs. 23.1±10.4 mg/dL) prior to the treatment, and no history of alcohol consumption. The only factor predictive of clinical success by multivariate analysis was low total bilirubin level at the time of endoscopic intervention, regardless of history of alcohol consumption [odds ratio 1.223 (95% confidence interval, 1.071-1.396), p=0.003]. The cut-off value of pre-endoscopic treatment total bilirubin level was 12.8 mg/dL for predicting the clinical prognosis. Median survival after endoscopic intervention in the clinical success group was notably longer than that in the clinical failure group (5.6 months vs. 1.5 months, p≤0.001).

Conclusion

Before endoscopic intervention, liver function, especially total bilirubin level, should be checked to achieve the best clinical outcome. Endoscopic intervention can be helpful to relieve jaundice in well selected patients with HCC.     

Suppression of human hepatocellular cancer cell proliferation by Brucea javanica oil-loaded liposomes via induction of apoptosis

Introduction

Hepatocellular carcinoma (HCC) is a type of malignancy with high incidence and poor prognosis. Brucea javanica is extracted from Simaroubaceae plants. It is found to have low toxicity but high anti-cancer efficiency. The aim of this study is to determine the effects of Brucea javanica oil-loaded liposomes (BJOL) on human hepatocellular cancer cell line HepG2. The related molecular mechanisms were determined.

Material and methods

Morphologic changes of HepG2 cells were observed by transmission electron microscope after treatment with BJOL in vitro. Cell proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay after cell treatment with different doses of BJOL. Flow cytometry was performed. Nude mice were divided into 4 groups randomly and treated with different doses of BJOL. The apoptosis hepatocellular carcinoma was detected by TUNEL.

Results

Proliferation of HepG2 was inhibited significantly by BJOL in a dose-dependent manner (2.5 mg/l or 5 mg/l). Compared with the animal models treated with the negative control, the animal models in the BJOL group had higher weight and lower metastasis rates (p < 0.01). The rate of apoptosis in hepatocellular carcinoma tissue of the BJOL groups was increased when compared with the control group (p < 0.05).

Conclusions

Brucea javanica oil-loaded liposomes inhibits proliferation of HepG2. The effect appears to be dose-dependent, possibly by inducing apoptosis of cancer cells.     

Co-expression patterns of Notch1, Snail,and p53 in grade III hepatocellular carcinoma with postoperative recurrence: a preliminary study

Background/Aims

We aimed to determine the association between the co-expression patterns of Notch1, Snail, and p53 proteins (NSP) and the postoperative prognosis of hepatocellular carcinoma (HCC).

Methods

The immunoblot data for molecular expression (147 HCC/corresponding non-HCC tissues and 15 dysplastic nodules) and the sequencing data for p53 mutations (110 HCCs) were obtained from our previous study. Data analyses were restricted to cases with HCC differentiation grade III (n=47), due to its high p53 mutation rate.

Results

Nineteen of the 47 patients (40.4%) -comprising 12 in the liver and 7 in distant organs-had relapsed at 1-2 years after surgery. There was no relationship between p53 mutation and postoperative recurrence in the grade III HCCs. Seven (87.5%) of the eight relapsed cases with Notch1, Snail, and p53 (wild) co-expression experienced recurrence only within the liver, and all tumors were smaller than 5 cm in diameter. Extrahepatic relapse occurred mostly in HCC patients with tumors larger than 5 cm in diameter, without any deviation in the NSP pattern.

Conclusions

The results of this preliminary study suggest that the co-expression of Notch1, Snail, and p53 (wild) is not inferior to the patterns with p53 mutation as an indicator of postoperative recurrence of grade III HCC.     

Efficacy and safety of metronomic chemotherapy for patients with advanced primary hepatocellular carcinoma with major portal vein tumor thrombosis

Background/Aims

Low-dose metronomic chemotherapy involves the frequent administration of comparatively low doses of cytotoxic agents with no extended breaks, and it may be as efficient as and less toxic than the conventional maximum tolerated dose therapy. This study evaluated the feasibility and therapeutic efficacy of metronomic chemotherapy in patients with advanced hepatocellular carcinoma (HCC) with major portal vein thrombosis (PVT).

Methods

Thirty consecutive HCC patients with major PVT with or without extrahepatic metastasis were prospectively allocated to metronomic chemotherapy consisting of epirubicin being infused through the correct hepatic artery at a dose of 30 mg/body surface area (BSA) every 4 weeks, and cisplatin (15 mg/BSA) and 5-fluorouracil (50 mg/BSA) every week for 3 weeks, with intervening 1 week breaks. The treatment response was assessed using response evaluation criteria in solid tumors (RECIST).

Results

In total, 116 cycles of metronomic chemotherapy were administered to the 30 patients, with a median of 3 cycles given to individual patients (range, 1-15 cycles). Six patients (20.0%) achieved a partial response and six patients (20.0%) had stable disease. The median time to disease progression and overall survival were 63 days (range, 26-631 days) and 162 days (95% confidence interval; range, 62-262 days), respectively. Overall survival was significantly associated with baseline alpha-fetoprotein level (P=0.001) and tumor response (P=0.005). The baseline alpha-fetoprotein level was significantly associated with the disease control rate (P=0.007). Adverse events were tolerable and managed successfully with conservative treatment.

Conclusions

Metronomic chemotherapy may be a safe and useful palliative treatment in HCC patients with major PVT.     

Growth rate of early-stage hepatocellular carcinoma in patients with chronic liver disease

Background/Aims

The goal of this study was to estimate the growth rate of hepatocellular carcinoma (HCC) and identify the host factors that significantly affect this rate.

Methods

Patients with early-stage HCC (n=175) who underwent two or more serial dynamic imaging studies without any anticancer treatment at two tertiary care hospitals in Korea were identified. For each patient, the tumor volume doubling time (TVDT) of HCC was calculated by comparing tumor volumes between serial imaging studies. Clinical and laboratory data were obtained from the medical records of the patients.

Results

The median TVDT was 85.7 days, with a range of 11 to 851.2 days. Multiple linear regression revealed that the initial tumor diameter (a tumor factor) and the etiology of chronic liver disease (a host factor) were significantly associated with the TVDT. The TVDT was shorter when the initial tumor diameter was smaller, and was shorter in HCC related to hepatitis B virus (HBV) infection than in HCC related to hepatitis C virus (HCV) infection (median, 76.8 days vs. 137.2 days; P=0.0234).

Conclusions

The etiology of chronic liver disease is a host factor that may significantly affect the growth rate of early-stage HCC, since HBV-associated HCC grows faster than HCV-associated HCC.     

Prevalence of angiotensin converting enzyme (ACE) gene insertion/deletion polymorphism in South Indian population with hypertension and chronic kidney disease

Context:

Chronic Kidney Disease (CKD) is associated with a high risk of developing further severe complications such as, cardiovascular disease and eventually End Stage Renal Disease (ESRD) leading to death. Hypertension plays a key role in the progression of renal failure and is also a chief risk factor for the occurrence of End Stage Renal Disease (ESRD).

Aim:

This study investigates the possible association of insertion (I) and deletion (D) polymorphism of ACE gene in patients of Chronic Kidney Disease (CKD) with and without hypertension (HT).

Settings and Design:

Total 120 participants with 30 members in each group (Control, HT, CKD and CKD-HT) were chosen followed by informed consent.

Materials and Methods:

Blood samples were collected and subjected to biochemical analyses and nested PCR amplification was performed to genotype the DNA, for ACE I/D using specific primers.

Statistical Analysis:

Statistical analyses were performed using SPSS version 13. Allele and genotypic frequency was calculated by direct gene counting method. Comparison of the different genotypes was done by using Chi square test. Odd''s ratios were calculated with a 95% confidence interval limit.

Results:

The ACE genotype were distributed as II, 27 (90%); DD, 2 (6.67%) and ID, 1 (3.33%) in control, II, 1 (3.33%); DD, 5 (16.67%) and ID, 24 (80%) in HT, II, 4 (13.33%); DD, 24 (80%) and ID, 2 (6.67%) in CKD and II, 0 (0%); DD, 2 (6.67%) and ID, 28 (93.33%) in CKD-HT group.

Conclusions:

D allele of ACE gene confers a greater role in genetic variations underlying CKD and hypertension. This result suggest that CKD patients should be offered analysis for defects in ACE I/D polymorphisms, especially if they are hypertensive.KEY WORDS: Allele, chronic kidney disease, hypertension, PCR, polymorphism of ACE gene     

Thrombocytopenia represents a risk for deterioration of liver function after radiofrequency ablation in patients with hepatocellular carcinoma

Background/Aims

We evaluated changes in liver function parameters and risk factors for the deterioration of liver function 12 months after percutaneous radiofrequency ablation (RFA) therapy in patients with hepatocellular carcinoma (HCC).

Methods

The subjects in this retrospective study comprised 102 patients with HCC who had undergone RFA therapy and exhibited no recurrence of HCC 12 months thereafter. Serial changes in serum total bilirubin and albumin, prothrombin time, and Child-Pugh score were evaluated before RFA and 3, 6, 9, and 12 months thereafter. Deterioration of liver function was defined when the Child-Pugh score increased by at least 2 at 12 months after RFA therapy. We determined the factors related to aggravation of liver function after RFA therapy.

Results

Liver function had deteriorated 12 months after RFA in 29 patients (28.4%). Serum albumin levels decreased significantly from before (3.7±0.1 g/dL, mean±SD) to 12 months after RFA therapy (3.3±0.1 g/dL, P=0.002). The Child-Pugh score increased significantly during the same time period (from 6.1±0.2 to 7.2±0.3, P<0.001). Pre-RFA thrombocytopenia (≤100,000/mm³) was revealed as a significant risk factor for the deterioration of liver function after RFA. However, no patients had episodes of bleeding as a complication of RFA.

Conclusions

Among the liver-function parameters, serum albumin level was markedly decreased in HCC patients over the course of 24 months after RFA therapy. A pre-RFA thrombocytopenia represents a major risk factor for the deterioration of liver function.     

A comparative study of high-dose hepatic arterial infusion chemotherapy and transarterial chemoembolization using doxorubicin for intractable,advanced hepatocellular carcinoma

Background/Aims

Transarterial chemoembolization (TACE) has long been used as a palliative therapy for unresectable hepatocellular carcinoma (HCC). High-dose hepatic arterial infusion chemotherapy (HAIC) has showed favorable outcomes in patients with intractable, advanced HCC. The aim of this study was to compare the effectiveness and safety of high-dose HAIC and conventional TACE using doxorubicin for advanced HCC.

Methods

The high-dose HAIC group comprised 36 patients who were enrolled prospectively from six institutions. The enrollment criteria were good liver function, main portal vein invasion (including vascular shunt), infiltrative type, bilobar involvement, and/or refractory to prior conventional treatment (TACE, radiofrequency ablation, or percutaneous ethanol injection), and documented progressive disease. Patients received 5-fluorouracil (500 mg/m² on days 1~3) and cisplatin (60 mg/m² on day 2 every 4 weeks) via an implantable port system. In the TACE group, 31 patients with characteristics similar to those in the high-dose HAIC group were recruited retrospectively from a single center. Patients underwent a transarterial infusion of doxorubicin every 4~8 weeks.

Results

Overall, 6 patients (8.9%) achieved a partial response and 20 patients (29.8%) had stable disease. The objective response rate (complete response+partial response) was significantly better in the high-dose HAIC group than in the TACE group (16.7% vs. 0%, P=0.030). Overall survival was longer in the high-dose HAIC group than in the TACE group (median survival, 193 vs. 119 days; P=0.026). There were no serious adverse effects in the high-dose HAIC group, while hepatic complications occurred more often in the TACE group.

Conclusions

High-dose HAIC appears to improve the tumor response and survival outcome compared to conventional TACE using doxorubicin in patients with intractable, advanced HCC.     

Influence of ezetimibe on selected parameters of oxidative stress in rat liver subjected to ischemia/reperfusion

Introduction

Ischemia/reperfusion (I/R) is considered to be one of the main causes of liver damage after transplantation. The authors evaluated the effect of ezetimibe on selected oxidative stress parameters in ischemic/reperfused (I/R) rat liver.

Material and methods

Rats were administered ezetimibe (5 mg/kg) (groups E and E-I/R) or saline solution (groups C and C-I/R) intragastrically for 21 days. Livers of animals in groups C-I/R and E-I/R were subjected to 60 min of partial ischemia (left lateral and median lobes) followed by 4 h of reperfusion. Alanine and asparagine aminotransferase (ALT, AST) activity was determined in blood before I/R and during reperfusion (at 15 and 240 min). After the reperfusion period, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) and glutathione peroxidase (GPx) were determined in liver homogenates using colorimetric methods.

Results

Ezetimibe caused a significant increase in GSH level in groups subjected to I/R (E-I/R (99.91 ±9.01) vs. C-I/R (90.51 ±8.87), p < 0.05). Additionally, under I/R the decrease of GPx activity in the drug-treated group was lower compared to the non-treated group (E-I/R (3.88 ±1.11) vs. E (5.31 ±1.83), p = 0.076). Neither ezetimibe nor I/R affected SOD or MDA levels. I/R produced a significant increase in aminotransferase levels (ALT240-0: C-I/R (42.23 ±43.56) vs. C (9.75 ±11.09), and E-I/R (39.85 ±26.53) vs. E (4.38 ±1.36), p < 0.05 in both cases; AST 240-0: E-I/R (53.87 ±17.23) vs. E (24.10 ±9.66), p < 0.05) but no effect of ezetimibe on those enzymes was found.

Conclusions

Ezetimibe demonstrates antioxidant properties in rat livers subjected to I/R. However, neither a hepatoprotective nor a hepatotoxic effect of ezetimibe was demonstrated, regardless of I/R.     

Impact of immunosuppressant therapy on early recurrence of hepatocellular carcinoma after liver transplantation

Background/Aims

The most commonly used immunosuppressant therapy after liver transplantation (LT) is a combination of tacrolimus and steroid. Basiliximab induction has recently been introduced; however, the most appropriate immunosuppression for hepatocellular carcinoma (HCC) patients after LT is still debated.

Methods

Ninety-three LT recipients with HCC who took tacrolimus and steroids as major immunosuppressants were included. Induction with basiliximab was implemented in 43 patients (46.2%). Mycophenolate mofetil (MMF) was added to reduce the tacrolimus dosage (n=28, 30.1%). The 1-year tacrolimus exposure level was 7.2 ± 1.3 ng/mL (mean ± SD).

Results

The 1- and 3-year recurrence rates of HCC were 12.9% and 19.4%, respectively. Tacrolimus exposure, cumulative steroid dosages, and MMF dosages had no impact on HCC recurrence. Induction therapy with basiliximab, high alpha fetoprotein (AFP; >400 ng/mL) and protein induced by vitamin K absence/antagonist-II (PIVKA-II; >100 mAU/mL) levels, and microvascular invasion were significant risk factors for 1-year recurrence (P<0.05). High AFP and PIVKA-II levels, and positive ¹⁸fluoro-2-deoxy-d-glucose positron-emission tomography findings were significantly associated with 3-year recurrence (P<0.05).

Conclusions

Induction therapy with basiliximab, a strong immunosuppressant, may have a negative impact with respect to early HCC recurrence (i.e., within 1 year) in high-risk patients.     

Propofol versus flunitrazepam for inducing and maintaining sleep in postoperative ICU patients

Context:

Sleep deprivation is a common problem on intensive care units (ICUs) influencing not only cognition, but also cellular functions. An appropriate sleep-wake cycle should therefore be maintained to improve patients’ outcome. Multiple disruptive factors on ICUs necessitate the administration of sedating and sleep-promoting drugs for patients who are not analgo-sedated.

Aims:

The objective of the present study was to evaluate sleep quantity and sleep quality in ICU patients receiving either propofol or flunitrazepam.

Settings and Design:

Monocentric, randomized, double-blinded trial.

Materials and Methods:

A total of 66 ICU patients were enrolled in the study (flunitrazepam n = 32, propofol n = 34). Propofol was injected continuously (2 mg/kg/h), flunitrazepam as a bolus dose (0.015 mg/kg). Differences between groups were evaluated using a standardized sleep diary and the bispectral index (BIS).

Statistical Analysis Used:

Group comparisons were performed by Mann-Whitney U-Test. P < 0.05 was considered to be statistically significant.

Results:

Sleep quality and the frequency of awakenings were significantly better in the propofol group (Pg). In the same group lower BIS values were recorded (median BIS propofol 74.05, flunitrazepam 78.7 [P = 0.016]). BIS values had to be classified predominantly to slow-wave sleep under propofol and light sleep after administration of flunitrazepam. Sleep quality improved in the Pg with decreasing frequency of awakenings and in the flunitrazepam group with increasing sleep duration.

Conclusions:

Continuous low-dose injection of propofol for promoting and maintaining night sleep in ICU patients who are not analgo-sedated was superior to flunitrazepam regarding sleep quality and sleep structure.     

Effect of clinical condition and mycophenolate mofetil on plasma retinol, α-tocopherol and β-carotene in renal transplant recipients

Introduction

Plasma antioxidant vitamins (retinol, α-tocopherol, β-carotene) were measured to establish the influence of clinical condition and mycophenolate mofetil (MMF) treatment on the nutritional status of renal transplant recipients.

Material and methods

In 106 adult patients plasma vitamins were measured and 24-h diet history questionnaires were conducted. The MMF influence on plasma vitamins was verified in 61 patients.

Results

The current dietary intakes of vitamins in daily food rations were lower than recommended. Plasma retinol was lower in patients suffering from gastrointestinal disorders (1.25 ±0.48 mg/l vs. 1.55 ±0.70 mg/l) and inversely associated with aminotransferases activity (p = 0.019) and creatinine clearance (p = 0.021). Retinol concentrations were positively associated with plasma creatinine (p = 0.027) and pharmacokinetic parameters of MMF phenyl glucuronide. β-Carotene concentrations were higher in women (0.39 ±0.46 mg/l vs. 0.28 ±0.23 mg/l; p = 0.041) and when MMF was co-administered with cyclosporine vs. tacrolimus (0.45 ±0.62 mg/l vs. 0.25 ±0.19 mg/l). Plasma α-tocopherol correlated negatively with the mycophenolic acid pre-dose concentration (p = 0.027) and was significantly lower in patients treated with calcineurin inhibitors (8.90 ±5.23 mg/l vs. 12.25 ±5.62 mg/l). A positive correlation was observed between α-tocopherol levels and aspartate aminotransferase (p = 0.006). In multivariate regression aspartate aminotransferase and MMF treatment significantly influenced retinol (p < 0.001).

Conclusions

The MMF treatment was associated with significantly lower retinol concentrations. The gastrointestinal disorders occurrence in MMF-treated patients may cause a decrease in retinol absorption. Diet adjustment and/or vitamin A supplementation should be considered.     

Fibroblast growth factor receptor isotype expression and its association with overall survival in patients with hepatocellular carcinoma

Background/Aims

Fibroblast growth factor signaling is involved in hepatocarcinogenesis. The aim of this study was to determine the fibroblast growth factor receptor (FGFR) isotype expression in hepatocellular carcinoma (HCC) and neighboring nonneoplastic liver tissue, and elucidate its prognostic implications.

Methods

Immunohistochemical staining of FGFR1, -2, -3, and -4 was performed in the HCCs and paired neighboring nonneoplastic liver tissue of 870 HCC patients who underwent hepatic resection. Of these, clinical data for 153 patients who underwent curative resection as a primary therapy were reviewed, and the relationship between FGFR isotype expression and overall survival was evaluated (development set). This association was also validated in 73 independent samples (validation set) by Western blot analysis.

Results

FGFR1, -2, -3, and -4 were expressed in 5.3%, 11.1%, 3.8%, and 52.7% of HCCs, respectively. Among the development set of 153 patients, FGFR2 positivity in HCC was associated with a significantly shorter overall survival (5-year survival rate, 35.3% vs. 61.8%; P=0.02). FGFR2 expression in HCC was an independent predictor of a poor postsurgical prognosis (hazard ratio, 2.10; P=0.02) in the development set. However, the corresponding findings were not statistically significant in the validation set.

Conclusions

FGFR2 expression in HCC could be a prognostic indicator of postsurgical survival.     

Blockade of CCN4 attenuates CCl4-induced liver fibrosis

Introduction

CCN4, also termed WNT-inducible signaling pathway protein-1 (WISP-1), has important roles in inflammation and tissue injury. This study aimed to investigate the effect of CCN4 inhibition using monoclonal anti-CCN4 antibody (CCN4mAb) on the liver injury and fibrosis in a mouse model of liver fibrosis.

Material and methods

The mouse liver fibrosis model was induced by carbon tetrachloride (CCl₄). Mice received vehicle (saline/olive oil) by subcutaneous injection, CCl₄ by subcutaneous injection or CCl₄ (subcutaneous) plus CCN4mAb by subcutaneous injection. The pro-inflammatory and pro-fibrotic factors were determined by Western blot. The biochemistry and histopathology, collagen deposition and nuclear factor (NF)-κB activity were also assessed.

Results

Chronic CCl₄ treatment caused liver injury and collagen accumulation. The expression levels of CCN4, pro-inflammatory and pro-fibrotic mediators as well as the activity of NF-κB were markedly increased. Treatment with CCN4mAb significantly inhibited CCl₄-induced CCN4 expression, leading to attenuated CCl₄-induced liver injury and the inflammatory response. CCN4 blockade also significantly reduced the formation of collagen in the liver and the expression of α-smooth muscle actin and transforming growth factor β1.

Conclusions

CCN4 inhibition by CCN4mAb in vivo significantly attenuated the CCl₄-induced liver injury and the progression of liver fibrosis. CCN4 may represent a novel therapeutic target for liver injury and fibrosis.     

Hyponatremia in critically ill patients

Context:

Hyponatremia is a common electrolyte disturbance in critically ill hence understanding its implications is important.

Aims:

This study was carried out to ascertain frequency, predisposing conditions and outcome in critically ill patients with hyponatremia on intensive care unit (ICU) admission.

Settings and Design:

This was an observational, prospective study of a series of ICU patients during a 12-month period.

Materials and Methods:

The patients were divided into two groups: Hyponatremic (serum sodium < 135 mmol/L) and Eunatremic groups (135-145 mmol/L). Clinical examination included volume status and drug history, biochemistries, clinical diagnosis and cause of hyponatremia.

Statistical Analysis Used:

Fisher''s exact test, unpaired t-tests Wilcoxon ranksum tests, profile-likelihood method, log-rank test and Kaplan—Meier curves were used. P < 0.05 were considered to be statistically significant.

Results:

In the hyponatremic group, the frequency of hyponatremia on ICU admission was 34.3%, most were euvolumic, 58.96%. Females comprised of 36.5%. The mean age was 60.4 ± 17.2. The Syndrome of inappropriate Antidiuretic Hormone (SIADH) criteria was met in ninety-one patients (36.25%), peumonia being the leading cause of SIADH. Patients with severe sepsis, elective surgery patients, renal failure and heart failure, cirrhosis of liver and subarachnoid hemorrhage were other more likely etiologic causes (P < 0.05). The hyponatremic group spent a longer time in the ICU (P = 0.02), had longer mechanical ventilator days (P < 0.05) and had an increased mortality rate (P = 0.01).

Conclusions:

Hyponatremia present on admission to the ICU is independent risk factors for poor prognosis.